DESCRIPTION: The goal of this research program is to develop an improved agent for use in oral health care products that will help prevent gingivitis and, in turn, may prevent progression to periodontal diseases. We have identified a new generation of proprietary salicylanilides, termed the 5-naphthoylsalicylanilides, as a potential source of this agent. The combined physicochemical and biological properties of this new generation of LAAD-type salicylanilides gives them several advantages over other drugs and formulations currently used for this purpose. These include a broad spectrum of antibiotic activity, particularly against cariogenic and periodontopathic bacteria, activity against biofilm (plaque) formation, topical anti-inflammatory activity, activity against several enzymes involved in soft tissue destruction, and a high degree of substantivity. These qualities, plus the patent status of the technology, make an optimized 5-naphthoylsalicylanilide an excellent candidate for development. In this amended Phase I application we plan to demonstrate the feasibility of developing an optimized 5-naphthoylsalicylanilide by comparing the activities of a focused series of compounds designed around our "lead" agent, NAlmF, in several in-vitro systems predictive of in-vivo efficacy and safety. From these data we will choose the three most promising compounds for scale up synthesis and preliminary in vivo efficacy evaluation in mouse models of acute inflammation and P.gingivalis-induced alveolar bone loss, and for oral safety in the rat. Based upon the results of these studies we will choose one "optimized" agent for progression to Phase II. In Phase II we intend to produce and analyze sufficient material for further testing of the optimized compound, develop experimental pharmaceutical rinse formulations containing the agent, determine the long-term chemical, microbiological and physical stability of the agent in its preferred formulation, and further evaluate safety and preclinical efficacy using additional models and dosage schemes to allow for IRB approval to evaluate the formulated agent in a "proof-of-principal" test in humans. We are seeking =Fast-Track" status for this application because we have a strategic alliance with a Fortune 500 Corporate Partner who will pursue this testing in humans and the subsequent development, manufacturing and marketing of our optimized agent should the studies proposed here and in Phase II prove successful. [unreadable] [unreadable]